There are currently more than 400,000 people undergoing maintenance hemodialysis (MHD) in the United States program. The mortality in this group of patients is unacceptably high. A majority of the deaths are due to cardiovascular diseases, followed by infectious complications and protein-energy wasting. Strategies to reduce the mortality of MHD patients, including those directed at traditional cardiovascular risk factors such as statins, have largely been ineffective. Inflammation has been implicated in the pathogenesis of atherosclerotic cardiovascular disease and protein-energy wasting. Biomarkers of the inflammatory state such as C-reactive protein (hsCRP) and interleukin-6 (IL-6) are elevated in MHD patients and are also robust predictors of cardiovascular events and mortality in this patient population. While anti-inflammatory interventions, especially specific anti-cytokin therapies have been used successfully to treat patients with inflammatory bowel disease, psoriasis and rheumatoid arthritis, and while encouraging studies have been reported in improving glycemic control and beta cell function in type 2 diabetes, there are only limited studies using these interventions in MHD patients. Our investigative group has performed a series of studies investigating the feasibility, safety, and efficacy of a number of anti-inflammatory therapies in MHD patients, including Interleukin-1 receptor antagonist (IL-1ra), Fish Oil (EPA+DHA), Vitamin E (gamma-tocopherol), alpha lipoic acid (ALA) and CoEnyzme Q10 in studies ranging from 14 patients to 300 patients. We have shown that amongst these interventions, IL-1ra and Fish Oil therapies have the most significant beneficial effects on inflammatory markers, such as hsCRP and IL- 6; whereas Vitamin E and ALA therapies do not influence inflammatory state in these patients. This grant application is submitted in response to the recent NIDDK RFA DK-12-010 (Novel Interventions to Reduce Morbidity and Mortality of Hemodialysis Patients - Safety and Other Early Phase Studies) and has the overarching aim of studying the safety, feasibility and efficacy of promising pharmacological and dialytic interventions in maintenance hemodialysis patients through a U01 collaboration mechanism. Our specific aims are 1) To test the efficacy of IL-1ra and Fish Oil on inflammatory biomarkers over 6 months through two separate randomized clinical trials in maintenance hemodialysis patients; 2) To test the safety and tolerability of IL-1ra and Fish Oil over 6 months through two separate randomized clinical trials in maintenance hemodialysis patients; 3) Create a collaborative network of investigators and dialysis facilities for efficient and swift subject recruitment for pilot and feasibility studies in maintenance hemodialysis patients. The ultimate goal of this application is to obtain critical elements of the study design and suitable interventin for a subsequent full-scale randomized controlled clinical trial in MHD patients testing rigorous clinical outcomes including morbidity and mortality.